Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811


Molecular Modelling and QSAR in the Discovery of HIV-1 Integrase Inhibitors

Author(s): Anna M. Almerico, Marco Tutone, Mario Ippolito, Antonino Lauria.


The treatment regimens for the HIV-1 have mainly included reverse transcriptase or protease inhibitors but their long-term clinical utility is limited by severe side effects and viral drug resistance. A new attractive target for chemotherapeutic intervention can be the Integrase enzyme, that mediates the integration of HIV-1 DNA into a host chromosome, for which there is no known counterparts in the host cell. A number of derivatives have been found to inhibit IN in in vitro assays, but no successful drug based on them has emerged so far, although many compounds have been proposed. Moreover most of the inhibitors do not belong to a very precise structural class: this fact makes these compounds a suitable target to be approached by all QSAR methods (classical and 3D) which therefore have been used to study the IN inhibitors. This review focuses on the molecular basis and rationale for developing integrase inhibitors and assesses the literature results of the chemometric study on classes of these inhibitors. Rational drug design by mean of the pharmacophore approach, rigid and flexible docking methods, and de novo design contributed to the identification of the most promising class of inhibitors, the DKAs. Moreover molecular dynamics studies were included since they can contribute to give further insight into the inhibitors binding modes already explored by means of the docking simulations.

Keywords: HIV-1 integrase inhibitors, QSAR, molecular modelling, pharmacophore, docking, de novo design, molecular dynamics

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Article Details

Year: 2007
Page: [214 - 233]
Pages: 20
DOI: 10.2174/157340907781695468
Price: $58